Low-dose corticosteroid and mycophenolate for primary treatment of minimal change disease.

BACKGROUND: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. AIM: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. DESIGN: A prospective, open-label, randomized clinical trial. METHODS: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). RESULTS: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. CONCLUSION: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.

Annual direct medical costs associated with diabetes-related complications in the event year and in subsequent years in Hong Kong.

AIM: To develop models to estimate the direct medical costs associated with diabetes-related complications in the event year and in subsequent years. METHODS: The public direct medical costs associated with 13 diabetes-related complications were estimated among a cohort of 128 353 people with diabetes over 5 years. Private direct medical costs were estimated from a cross-sectional survey among 1825 people with diabetes. We used panel data regression with fixed effects to investigate the impact of each complication on direct medical costs in the event year and subsequent years, adjusting for age and co-existing complications. RESULTS: The expected annual public direct medical cost for the baseline case was US$1,521 (95% CI 1,518 to 1,525) or a 65-year-old person with diabetes without complications. A new lower limb ulcer was associated with the biggest increase, with a multiplier of 9.38 (95% CI 8.49 to 10.37). New end-stage renal disease and stroke increased the annual medical cost by 5.23 (95% CI 4.70 to 5.82) and 5.94 (95% CI 5.79 to 6.10) times, respectively. History of acute myocardial infarction, congestive heart failure, stroke, end-stage renal disease and lower limb ulcer increased the cost by 2-3 times. The expected annual private direct medical cost of the baseline case was US$187 (95% CI 135 to 258) for a 65-year-old man without complications. Heart disease, stroke, sight-threatening diabetic retinopathy and end-stage renal disease increased the private medical costs by 1.5 to 2.5 times. CONCLUSIONS: Wide variations in direct medical cost in event year and subsequent years across different major complications were observed. Input of these data would be essential for economic evaluations of diabetes management programmes.

Downregulation of renal tubular Wnt/ß-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy.

Studies on the role of Wnt/ß-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal ß-catenin expression in mice with overload proteinuria in which ß-catenin was upregulated at the early stage (4 weeks after disease induction) but abrogated at the late phase (8 weeks). Acute albuminuria was observed at 1 week after bovine serum albumin injection, followed by partial remission at 4 weeks that coincided with overexpression of renal tubular ß-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular ß-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular ß-catenin expression at these time points. In vitro, a similar trend in ß-catenin expression was observed in human kidney-2 (HK-2) cells with acute (upregulation) and prolonged (downregulation) exposure to albumin. Induction of a proapoptotic phenotype by albumin was significantly enhanced by silencing ß-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular ß-catenin signaling pathway. The effect of Dkk-3 on ß-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular ß-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.

Therapeutic Effects of Herbal Chemicals in Traditional Chinese Medicine on Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia that leads to increasing death and mental disability among humans. Current therapy of AD mainly relies on the use of acetylcholinesterase inhibitors (AChEIs) or antagonists of N-methyl-D-aspartate receptors (NMDARs), which only relieve the symptoms of the disease but not halt its progression. Nevertheless, Traditional Chinese medicines (TCM) are highly prized as many bioactive components isolated from TCM are beneficial for treating AD. In this review, we summarize the latest information on TCM and the bioactive components according to their mechanistic role in alleviating AD. They act as modulators of α- and ß-secretases, and inhibitors of betaamyloid (Aß) aggregation. Some of them suppress Aß-induced neuronal cytotoxicity and inflammation. Hence, this work has demonstrated the feasibility of applying TCM in AD therapy and the possibility of screening of constituents in TCM in the near future.

Progressive outer retinal necrosis in a renal transplant recipient: a rare treatment success.

Renal transplant recipients (RTRs) are subject to a variety of opportunistic infections. We present a rare case of varicella zoster virus-derived progressive outer retinal necrosis in an RTR, who presented with painless visual blurring. This clinical entity heralds an extremely poor visual prognosis and is an important condition to consider in any immunocompromised host. Early diagnosis by aqueous fluid sampling and immediate institution of combined systemic and intravitreal antiviral therapy was successful in this individual.

Current practices in the management of diabetic nephropathy.

The social and economic burden of treating patients with diabetes mellitus (DM) is rapidly rising. Current projections estimate the global prevalence of individuals with DM to rise from 6.4% (285 million) in 2010 to 7.7% (439 million) in 2030.1 The main problem with this disease entity is its propensity to incur macro- and micro-vascular complications over time, including diabetic nephropathy (DN). Diabetic nephropathy affects approximately one-third of individuals with diabetes. It is the leading cause of end-stage renal disease (ESRD) worldwide, accounting for 42% of all patients on renal replacement therapy (RRT) in the United States.2 The magnitude of this problem has continued to grow in the face of an inexorable rise in the number of diabetic patients. The search for therapeutic modalities to stem this tide remains the quest of many nephrologists. One of the hallmarks of DN is increased urinary protein excretion, and microalbuminuria has long been proposed as an early manifestation of this disease.3,4 Albuminuria and chronic kidney disease (CKD) are strong determinants of cardiovascular disease and to a large extent, the survival of patients with DN is determined by cardiovascular morbidity. Although there remains no cure at present, treatment options to prevent or slow disease progression are available. In this update, we aim to address the current armamentarium in the management of DN.

Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy.

Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins have renoprotective effects. We studied the cellular mechanisms for this effect in adriamycin-treated mice receiving captopril, losartan, simvastatin, or their combinations. The mice developed albuminuria, renal insufficiency, and parenchymal inflammation/fibrosis accompanied by overexpression of intrarenal converting enzyme and angiotensin II. Only captopril consistently improved these abnormalities and reduced the cortical expression of several proinflammatory and profibrotic factors including transforming growth factor-beta (TGF-beta). These effects were independent of blood pressure, accompanied by increased urine N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels, and the restoration of renal angiotensin-converting enzyme and angiotensin II to baseline levels. Losartan or simvastatin alone or together had no effect, and their addition to captopril did not enhance protection. In vitro, angiotensin II stimulated TGF-beta in renal tubular cells via mitogen-activated protein kinase (MAPK) signaling. Captopril or Ac-SDKP suppressed angiotensin II-induced MAPK activation and TGF-beta secretion. Angiotensin-converting enzyme inhibition confers renoprotection in adriamycin nephropathy by reducing intrarenal angiotensin II and augmenting Ac-SDKP expression that together attenuate MAPK signaling and its downstream proinflammatory and fibrogenic properties. The addition of receptor blocker and/or statin failed to potentiate such effects.

Rhodococcus lung abscess complicating kidney transplantation: successful management by combination antibiotic therapy.

In this report, a renal transplant recipient with Rhodococcus lung abscess is described. A high clinical suspicion and appropriate combination antibiotic therapy obviated the need for surgical intervention and was associated with a good clinical outcome. The optimal regimen of combination antibiotic therapy is discussed.

A pilot study on tacrolimus treatment in membranous or quiescent lupus nephritis with proteinuria resistant to angiotensin inhibition or blockade.

Persistent proteinuria in patients with quiescent lupus can result from membranous lupus nephritis and/or glomerular scarring following previous flares. This pilot study examined the effects of tacrolimus over two years in six patients with membranous/inactive lupus nephritis and persistent proteinuria despite angiotensin inhibition/blockade. Tacrolimus treatment reduced proteinuria and increased serum albumin (time effect, P = 0.047 and 0.032 respectively). Compared with baseline levels, proteinuria improved by more than 50% in five patients (83.3%) and hypoalbuminaemia was corrected in four patients. The efficacy was most prominent in four patients with biopsy-proven membranous lupus nephritis, whose protienuria improved by over 80%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment, despite non-excessive blood levels. These data suggest that tacrolimus is an effective treatment for proteinuria due to membranous lupus nephritis, but should probably be reserved for patients who are refractory to other non-nephrotoxic treatments, in view of the potential risk of subclinical nephrotoxicity.

Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state.

We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We established in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PTEC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells to supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can differentially modulate the expression of chemokine receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.

Leptin induces TGF-beta synthesis through functional leptin receptor expressed by human peritoneal mesothelial cell.

Marked increase in leptin concentration in spent peritoneal dialysate has been reported following continuous ambulatory peritoneal dialysis treatment. The present study was designed to determine whether functional leptin receptor is expressed by human peritoneal mesothelial cells and if so, the possible implication in dialysis. Expression of leptin receptors in cultured mesothelial cells and omental tissue was examined. The effect of leptin on the production of transforming growth factor-beta (TGF-beta) by mesothelial cells in the presence or absence of high glucose was determined using in vitro culture model of human peritoneal mesothelial cells and adipocytes. The signaling mechanism involved in leptin-induced TGF-beta synthesis by mesothelial cells was studied. Both mRNA and protein of the full-length leptin receptor are constitutively expressed in mesothelial cells. The leptin receptor expression in mesothelial cells was upregulated by glucose but not leptin. In adipocytes, glucose increased the mRNA expression and synthesis of leptin. The Janus kinase-signal transducers and activation (JAK-STAT) signal transduction pathway in mesothelial cells was activated by either exogenous or adipocytes-derived leptin. Exogenous leptin induced the release of TGF-beta by mesothelial cells. The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression. Our novel findings reveal that functional leptin receptor is present on human peritoneal mesothelial cells. The leptin-induced TGF-beta synthesis in mesothelial cells is associated with the expression of leptin receptor and the activation of the JAK-STAT signal transduction pathway.

Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products.

Autoclaving peritoneal dialysate fluid (PDF) degrades glucose into glucose degradation products (GDPs) that impair peritoneal mesothelial cell functions. While glycation processes leading to formation of advanced glycation end-products (AGE) were viewed commonly as being mediated by glucose present in the PDF, recent evidence indicates that certain GDPs are even more powerful inducers of AGE formation than glucose per se. In the present study, we examined the expression and modulation of AGE receptors on human peritoneal mesothelial cells (HPMC) cultured with GDPs, conventional PDF or PDF with low GDP content. HPMC cultured with GDPs differentially modulated AGE receptors (including RAGE, AGE-R1, AGE-R2 and AGE-R3) expression in a dose-dependent manner. At subtoxic concentrations, GDPs increased RAGE mRNA expression in HPMC. 2-furaldehyde (FurA), methylglyoxal (M-Glx) and 3,4-dideoxy-glucosone-3-Ene (3,4-DGE) increased the expression of AGE-R1 and RAGE, the receptors that are associated with toxic effects. These three GDPs up-regulated the AGE synthesis by cultured HPMC. In parallel, these GDPs also increased the expression of vascular endothelial growth factor (VEGF) in HPMC. PDF with lower GDP content exerted less cytotoxic effect than traditional heat-sterilized PDF. Both PDF preparations up-regulated the protein expression of RAGE and VEGF. However, the up-regulation of VEGF in HPMC following 24-h culture with conventional PDF was higher than values from HPMC cultured with PDF containing low GDP. We have demonstrated, for the first time, that in addition to RAGE, other AGE receptors including AGE-R1, AGE-R2 and AGE-R3 are expressed on HPMC. Different GDPs exert differential regulation on the expression of these receptors on HPMC. The interactions between GDPs and AGE receptors may bear biological relevance to the intraperitoneal homeostasis and membrane integrity.

Post-transplantation lymphoproliferative disease in Chinese: the Queen Mary Hospital experience in Hong Kong.

Post-transplantation lymphoproliferative disease (PTLD) is an unique iatrogenic complication after bone marrow transplantation (BMT) and solid organ transplantation (SOTx). The pattern of EBV related lymphoma in Chinese is different from Caucasians. We surveyed the incidence, clinical and pathological spectrum of PTLD among 541 cases of allogeneic BMT, 145 cases of renal transplant, 35 cases of heart/lung transplantation and 146 cases of orthotopic liver transplantation (OLT). From 1994 to 2001, 13 consecutive cases of PTLD were diagnosed, ranging from disseminated NK cell lymphoma to localized plasmacytoma. Both donor and recipient derived PTLD was documented. Disease was often heralded by cytomegaloviral disease and antithymocyte globulin (ATG) usage. Two cases were diagnosed post-mortem, and six patients died of PTLD at a median of 3 months. Complete and partial remission was only achieved in 3 and 2 cases, respectively, despite a range of treatment (reduced immunosuppression, explantation, radiotherapy, combination chemotherapy, donor lymphocytes, autologous marrow infusion and rituximab). Most responding patients died subsequently of rejection, infection and graft versus host disease (GVHD). The incidence of PTLD is not increased in Chinese patients. However, some patients may be at increased risk, especially mismatched allogeneic BMT, parental OLT (especially involving young infants) and heavy ATG exposure.